Inhibition of human tumor growth by intraperitoneal immunotoxins in nude mice.
Intracavitary administration of immunotoxins may play a role in the control of malignant effusions. Selection of immunotoxins for this form of therapy is based on their prior evaluation in preclinical studies. Monoclonal antibodies (mAb) 454A12 (antitransferrin receptor), and 260F9 are directed against antigens which are present on tumor cells in pleural and peritoneal effusions of patients with adenocarcinoma of the breast and ovary. In the present study, immunotoxins derived by conjugating these mAb to recombinant ricin A (rRA) were shown to be cytotoxic to human ovarian adenocarcinoma HEY cells in vitro and in vivo. In the in vitro assay 454A12-rRA and 260F9-rRA were 1000-fold and 10-fold, respectively, more cytotoxic than free rRa against HEY cells, and both immunotoxins were potentiated approximately 1000-fold by monensin. For in vivo studies HEY cells were injected i.p. into nude mice at a challenge dose (3 x 10(5) cells) which produced carcinomatosis with ascites, leading to death 30 days following injection. Administration of 454A12-rRA i.p. following the challenge dose resulted in a complete cure, whereas administration of 260 F9-rRA with monensin significantly prolonged survival. The greater cytotoxicity of 454A12-rRA than 260F9-rRA against HEY cells could be accounted for by the greater number of binding sites and higher internalization rate for 454A12-rRA and mAb 454A12 than 260F9-rRA and mAb 260F9, respectively. These results suggest a potential role for 454A12-rRA and 260F9-rRA plus monensin in the intracavitary therapy of malignant effusions associated with carcinoma of breast and ovary. In the case of 260F9-rRA, this represents the first preliminary indication of the suitability of this immunotoxin for intracavitary therapy of malignancies.
Marks
A
A
Banting and Best Department of Medical Research, University of Toronto, Ontario, Canada.
Ettenson
D
D
Bjorn
M J
MJ
Lei
M
M
Baumal
R
R
D000230:Adenocarcinoma / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008985:Monensin / Q000008:administration & dosage; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000628:therapy*; D012276:Ricin / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D012276:Ricin; D008985:Monensin